SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Opidol 100 mg prolonged-release tablets
Opidol 150 mg prolonged-release tablets
Opidol 200 mg prolonged-release tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 100 mg of tramadol hydrochloride.
Each prolonged-release tablet contains 150 mg of tramadol hydrochloride.
Each prolonged-release tablet contains 200 mg of tramadol hydrochloride.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Opidol 100 mg tablets are off-white, round, biconvex tablets, 9.0 mm in diameter
Opidol 150 mg tablets are off-white, capsule-shaped tablets, 14.0 mm in length
Opidol 200 mg tablets are off-white, capsule-shaped tablets, 17.5 mm in length
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of moderate to severe pain.
4.2 Posology and method of administration
The dose should be adjusted to the severity of the pain and the individual clinical
response of the patient.
Adults and adolescents 12 years and older:
The usual initial dose is one 100 mg Prolonged-release Tablet, twice daily, in the
morning and evening. The dosage interval must not be less than 8 hours.
If the pain relief is insufficient, the dose may be increased to:
one 150 mg prolonged-release tablet, twice daily or
one 200 mg prolonged-release tablet, twice daily.
The recommended doses are intended as a guideline.
Opidol prolonged-release tablets should be swallowed whole without breaking or
chewing, with a sufficient amount of liquid. The tablets can be taken with or without
The dose used should be the lowest dose that provides pain relief. Daily doses of 400
mg active substance should not be exceeded, except in special clinical circumstances.
Under no circumstances should Opidol prolonged-release tablets be used for longer
than absolutely necessary.
If long-term pain treatment with tramadol is necessary in view of the nature and
severity of the illness, then careful and regular monitoring should be carried out (if
necessary with breaks in treatment) to establish whether, and to what extent, further
treatment is necessary.
Opidol prolonged-release tablets are not suitable for children under the age of 12
A dose adjustment is not usually necessary in elderly patients (up to 75 years) without
clinically manifest hepatic or renal insufficiency. In elderly patients (over 75 years)
elimination may be prolonged. Therefore, if necessary, the dosage interval is to be
extended according to the patients requirements.
Renal impairment, dialysis and hepatic impairment:
In patients with serious renal or hepatic impairment the use of Opidol tablets are not
recommended. In moderate cases, a prolongation of the dosage interval may be
considered since elimination is delayed.
Opidol prolonged-release tablets must not be used in:
hypersensitivity to tramadol, or any excipients in the tablet (see section 6.1),
in acute intoxication with alcohol, hypnotics, analgesics, opioids or
psychotropic medicinal products.
in patients receiving MAO-inhibitors (such as moclobemide), or within
2weeks of their withdrawal.
in patients who are suffering from inadequately controlled epilepsy
Opidol prolonged-release tablets must not be used for narcotic withdrawal treatment.
4.4 Special warnings and precautions for use
Opidol prolonged-release tablets must be used with caution in patients dependent on
opioids (for example, morphine, diamorphine and codeine) , patients suffering head
injuries, shock, decreased level of consciousness of unknown origin, disturbances of
the respiratory centre or function, or increased intracranial pressure.
In patients sensitive for opioids the medicinal product should be used cautiously.
Convulsions have been reported at recommended dose levels and the risk may be
increased at doses exceeding the usual upper daily dose limit (400 mg).
The risk of convulsions may increase in patients taking tramadol and concomitant
medicinal products that can lower the seizure threshold (see section 4.5. ). Patients
with a history of epilepsy or those susceptible to seizures should only be treated with
tramadol if there are compelling reasons.
Tramadol has a low dependence potential. On long-term use tolerance, psychological
and physical dependence may develop.
Reports of dependence and abuse have been less frequent. Because of this potential
the clinical need for continued analgesic treatment should be reviewed regularly. In
patients with a tendency to drug abuse or dependence, treatment should be for short
periods under strict medical supervision.
Tramadol is not a suitable substitute in opioid dependent patients. The medicinal
product does not suppress morphine withdrawal symptoms although it is an opioid
4.5 Interaction with other medicinal products and other forms of interaction
Opidol prolonged-release tablets must not be combined with mono amino oxidase
(MAO) inhibitors (see section 4.3). Patients taking MAO inhibitors within 14 days
prior to administration of the opioid pethidine have experienced life-threatening
interactions that affect the central nervous system and respiratory and cardiovascular
function. It is possible that tramadol hydrochloride may cause similar interactions
with MAO inhibitors.
Concomitant use of Opidol prolonged-release tablets with other centrally acting
active substances, including alcohol, may potentiate the central nervous system
effects (see section 4.8).
The results of pharmacokinetic studies have so far shown that on the concomitant or
previous administration of cimetidine (enzyme inhibitor) clinically relevant
interactions are unlikely to occur.
Simultaneous or previous administration of carbamazepine (enzyme inducer) may
reduce the analgesic effect and shorten the duration of action.
In a limited number of pre-and postoperative studies, administration of the antiemetic
5-HT3 antagonist ondansetron increased the need of tramadol in patients with
The combination of mixed agonists/antagonists (e.g. buprenorphine, nalbuphine,
pentazocine) and tramadol is not recommended because it is theoretically possible
that the analgesic effect of a pure agonist is attenuated under these circumstances.
Tramadol may induce convulsions and may increase the potential for selective
serotonin re-uptake inhibitors, tricyclic antidepressants, anti-psychotics and other
seizure threshold lowering active substances to cause convulsions.
Isolated cases of serotonergic syndrome have been reported with the therapeutic use
of tramadol in combination with other serotonergic agents such as selective serotonin
re-uptake inhibitors (SSRIs).
Serotonergic syndrome can be manifested by symptoms such as confusion,
restlessness, fever, sweating, ataxia, hyperreflexia, myoclonia and diarrhoea.
Withdrawal of the serotonergic agent usually produces a rapid improvement.
Medicinal treatment depends on the nature and severity of symptoms.
Caution must be exercised during concomitant treatment with tramadol and coumarin
derivatives (e.g. warfarin) due to reports of increased international normalisation ratio
(INR) and ecchymoses in some patients.
Other medicinal products with a known inhibiting effect on CYP3A4, such as
ketoconazole, ritonavir and erythromycin, could inhibit the metabolism of tramadol
(N-demethylation) and probably also the metabolism of the active O-demethyled
metabolite. The clinical relevancy of this interaction has not been investigated. (See
4.8 Undesirable effects).
4.6 Fertility, pregnancy and lactation
Animal tests with very large concentrations of tramadol showed effects on the
development of the organs, bone formation and mortality of the neonate.
Teratogenic effects have not been found. Tramadol crosses the placenta.
Insufficient data are available to assess the safety of tramadol in pregnancy. Therefore
Opidol prolonged-release tablets must not be used during pregnancy.
Tramadol – administered before or during birth – does not affect uterine contractility.
In neonates it may induce changes in the respiratory rate which are usually not
When breastfeeding about 0.1 % of the maternal tramadol dose is excreted in milk.
Administration of Opidol prolonged-release tablets is not advised while
In case of a single administration of tramadol it is not usually required to interrupt
4.7 Effects on ability to drive and use machines
Opidol prolonged-release tablets may cause dizziness and/or drowsiness and
therefore, even when used according the directions, can influence the ability to drive
and use machines. This effect may be potentiated by alcohol, at the beginning of
treatment, when switching the active substance, and on concomitant use of other
CNS-depressant or anti-histamines. If patients are affected they should be warned not
to drive or operate machinery.
4.8 Undesirable effects
The most commonly reported adverse drug reactions are nausea and dizziness, both
occurring in more than 10% of patients.
Immune system disorders
Rare (>1/10000, <1/1000): Allergic reactions (e.g. dyspnoea, bronchospasm,
wheezing, angioneurotic oedema) and anaphylaxis
Metabolism and nutrition disorders
Rare (>1/10000, < 1/1000): changes in appetite
Rare (>1/10000, <1/1000): hallucinations, anxiety, confusion, sleep disturbances and
Psychiatric undesirable effects may vary individually in intensity and nature
(depending on personality and duration of medication). These include changes in
mood (usually elation, occasionally dysphoria), changes in activity (usually
suppression, occasionally increase) and changes in cognitive and sensorial capacity
(e.g. decision behaviour, perception disorders). Tramadol can cause dependence.
Symptoms of withdrawal reactions, similar to those occurring during opiate
withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia,
hyperkinesias, tremor and gastrointestinal symptoms.
Nervous system disorders
Very common (> 1/10): dizziness
Common (>1/100, <1/10): headache, drowsiness
Rare (>1/10000, < 1/1000): paraesthesia, tremor, epileptiform convulsions.
Very rare (< 1/10000): vertigo
Epileptiform convulsions occurred mainly after administration of high doses of
tramadol or after concomitant treatment with active substances which can lower the
seizure threshold or themselves induce cerebral convulsions (see section 4.4 and 4.5).
Rare (>1/10000, <1/1000): blurred vision
Uncommon (>1/1000, <1/100 ): effects on cardiovascular regulation (palpitation,
tachycardia). These adverse reactions may occur especially on intravenous
administration and in patients who are physically stressed.
Rare (>1/10000, <1/1,000): bradycardia
Uncommon (>1/1000, <1/100): postural hypotension or cardiovascular collapse
Rare (>1/10000, <1/1,000): increase in blood pressure.
Very rare (<1/10000): flushing
Respiratory, thoracic and mediastinal disorders
Worsening of asthma has also been reported, though a causal relationship has not
Rare (>1/10000, <1/1000):: Dyspnoea, respiratory depression
If the recommended doses are considerably exceeded and other centrally depressant
active substances are administered concomitantly (see section 4.5 "Interaction with
other medicinal products and other forms of interaction") respiratory depression may
Very common (>1/10): vomiting, nausea
Common (>1/100, <1/10): constipation, dry mouth.
Uncommon (>1/1000, <1/100): Retching, gastrointestinal irritation (a feeling of
pressure in the stomach, bloating, diarrhoea).
Very rare (<1/10000), including isolated reports of an increase in liver enzyme values
has been reported after use of tramadol.
Skin and subcutaneous tissue disorders
Common (>1/100, <1/10): sweating
Uncommon (>1/1,000, <1/100): dermal reactions (e.g. pruritus, rash, urticaria)
Musculoskeletal, connective tissue and bone disorders
Rare (>1/10000, <1/1000): motorial weakness
Renal and urinary disorders
Rare (>1/10000, <1/1000): micturition disorders (difficulty in passing urine and
Common (>1/100, <1/10): fatigue
Withdrawal symptoms, similar to those that occur in association with opiate
withdrawal, may manifest as follows: agitation, anxiety, nervousness, insomnia,
hyperkinesia, tremor and gastrointestinal disturbances. Other symptoms which have
rarely been observed in connection with the discontinuation of tramadol treatment
include: panic attacks, severe anxiety, hallucinations, paresthesia, tinnitus and
unusual CNS symptoms.
In tramadol intoxication, in principle, the same symptoms occur as for all other
centrally acting analgesics (opioids). In particular, these include miosis, vomiting,
cardiovascular collapse, depression of consciousness leading to coma, convulsions,
respiratory depression leading to respiratory failure.
General emergency measures are applicable.
These include protection of the airway, maintenance of respiration and cardiovascular
circulation depending on the symptoms. In addition activated charcoal can be
considered. The antidote for respiratory depression is naloxone.
In animal tests naloxone proved to be ineffective against convulsions. In that case
diazepam should be administered intravenously.
Tramadol is only minimally removed from plasma using haemodialysis or
haemofiltration. Therefore treatment of acute overdose of tramadol using
haemodialysis or haemofiltration alone is not a suitable way of detoxification.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics, other opioids
ATC code: N02AX02
Tramadol is a centrally acting opioid analgesic.
It is a non-selective, complete agonist of μ-, δ- and κ- opioid receptors with a higher
affinity for μ-receptors. Other mechanisms contributing to the analgesic effect are the
inhibition of the neural noradrenalin reuptake and an enhanced release of serotonin.
Tramadol has an antitussive action.
Contrary to morphine, tramadol does not suppress respiration in analgesic doses over
a large range.
In addition gastrointestinal motility is less affected.
Effects on the cardiovascular system tend to be minor.
The potency of tramadol is reported to be 1/10 to 1/6 that of morphine.
5.2 Pharmacokinetic properties
More than 90% of tramadol is absorbed after oral administration.
The mean absolute bioavailability is approximately 70 %, irrespective of concomitant
intake of food.
The difference between absorbed and non-metabolised available tramadol is probably
due to low first-pass effect. The first pass-effect after oral administration is a
maximum of 30%.
Tramadol has a high tissue affinity (V_d,β = 203 ± 40 l). Protein binding is about
It has been found that after administration of the 100mg Prolonged-release Tablets the
maximum peak plasma concentration C_max 141 ± 40 ng/ml was reached after 4.9
hours. After administration of the 200mg Prolonged-release Tablets a C_max of 260
± 62 ng/ml was reached after 4.8 hours.
Tramadol passes the blood-brain and placental barrier. Very small amounts of the
active substance and its O-demethyl derivative are found in the breast-milk (0.1% and
0.02% respectively of the applied dose).
Elimination of half-life t½β is approximately 6 h, irrespective of the mode of
administration. In patients above 75 years of age it may be prolonged by a factor of
In humans tramadol is mainly metabolised by means of N- and O-demethylation and
conjugation of the O-demethylation products with glucuronic acid. The enzymes
involved in the metabolism of tramadol are the cytochrome P450 isoenzymes,
CYP3A4 and CYP2D6. Only O-desmethyltramadol is pharmacologically active.
There are considerable inter-individual quantitative differences between the other
metabolites. So far, eleven metabolites have been found in the urine. Animal
experiments have shown that O-desmethyltramadol is more potent than the parent
substance by the factor 2-4. Its half life t½β (6 healthy volunteers) is 7.9 h (range 5.4-
9.6 h) and is approximately that of tramadol.
The inhibition of one or both isoenzymes, CYP3A4 and CYP2D6 involved in the
metabolism of tramadol, may affect the plasma concentration of tramadol or its active
metabolite. The clinical consequences of any such interactions are not known.
Tramadol and its metabolites are almost completely excreted via the kidneys.
Cumulative urinary excretion is 90% of the total radioactivity of the administered
dose. In cases of impaired hepatic or renal function the half-life may be slightly
prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h
(tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol), in an extreme case 22.3 h and 36
h respectively were found. In patients with renal insufficiency (creatinine clearance <
5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case 19.5 h and
43.2 h, respectively.
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.
The relationship between serum concentrations and the analgesic effect is
dosedependent, but varies considerably in isolated cases. A serum concentration of
100 - 300 ng/ml is usually effective.
5.3 Preclinical safety data
On repeated oral and parenteral administration of tramadol for 6 to 26 weeks to rats
and dogs, and oral administration for 12 months in dogs, there was no evidence of
changes caused by the active substance in haematogical, clinico-chemical or
Central nervous manifestations only occurred after high doses considerably above the
therapeutic range: restlessness, salivation, convulsions, and reduced weight gain.
Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight
respectively, and dogs rectal doses of 20 mg/kg body weight without any reactions.
In rats tramadol dosages from 50 mg/kg/day upwards caused toxic effects in dams
and raised neonate mortality. In the offspring retardation occurred in the form of
ossification disorders and delayed vaginal and eye opening. The fertility of male rats
was not influenced.
After higher doses (from 50 mg/kg/day upwards) females exhibited a reduced
In rabbits, toxic effects occurred as of 125 mg/kg in the mother and skeleton disorders
in the young.
In some in-vitro test systems there was evidence of mutagenic effects.
In-vivo studies showed no such effects. According to knowledge gained so far,
tramadol can be classified as non-mutagenic.
Experiments have been performed on rats and mice with regard to the tumorigenic
potential of tramadol.
The study in rats showed no evidence of any substance-related increase in the
incidence of tumours.
In the study in mice there was an increased incidence of liver cell adenomas in male
animals (a dose-dependent, non-significant increase from 15 mg/kg upwards) and an
increase in pulmonary tumours in females of all dosage groups (significant, but not
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium hydrogen phosphate dihydrate
Colloidal anhydrous silica.
6.3 Shelf life
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Cartons consisting of:
Al – PVC / PVdC blisters
Packs of 10, 20, 30, 50, 60, 100, 150 tablets.
Tablet container consisting of: Polypropylene body and closure with aluminium
Pack size: 100 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Brown & Burk UK Ltd
5, Marryat Close
8 MARKETING AUTHORISATION NUMBER(S)
To be completed nationally.
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
10 DATE OF REVISION OF THE TEXT